This invention relates to novel thienopyrimidine derivatives having A2B receptor antagonistic activity, to the use of such compounds in medicine, in relation to the treatment of disorders which are responsive to antagonism of the A2B receptor such as nociception, asthma, COPD, inflammatory disorders, diabetes, diabetic retinopathy and cancer, and to pharmaceutical compositions containing such compounds.
Adenosine is a naturally occurring purine nucleoside, the effects of which include stimulation of nociception afferents, bronchconstriction, immunosupression, vasodilation, inhibition of platelet aggregation, cardiac depression and inhibition of neurotransmitter release.
Adenosine produces a wide range of pharmacological effects mediated by activation of specific cell surface receptors, which are members of the G-protein coupled receptor family. Four subtypes of adenosine receptors have been identified, designated A1, A2A, A2B and A3.
The A2B adenosine receptor subtype is coupled to the Gs G-protein and stimulates adenylyl cyclase activity. Although significant advancement has been made in the understanding of the molecular pharmacology and physiology of A2B adenosine receptors, due to the lack of highly potent and selective ligands for this receptor subtype, many questions about the patho-physiological role of A2B receptors are yet to be resolved (Feoktistov and Biaggioni, Pharmacological Reviews (1997), 49(4), 381-402).
A2B receptors have been implicated in:                (i) the regulation of mast cell secretion (Feoktistov and Biaggioni, Journal of Clinical Investigation (1995), 96(4), 1979-86).        (ii) pain (Abo-Salem et al., Journal of Pharmacology and Experimental Therapeutics (2004), 308(1), 358-366.).        (iii) inflammation (Yang et al., Journal of Clinical Investigation (2006), 116(7), 1913-1923).        (iv) cancer (Zeng et al., Drug Development Research (2003), 58(4), 405-411).        (v) diabetes (Harada et al., Journal of Medicinal Chemistry (2001), 44(2), 170-179).        (vi) gene expression (Boyle et al., Arthritis & Rheumatism (1996), 39(6), 923-930).        (vii) cell growth (Dubey et al., Hypertension (1996), 27(3 Pt 2), 786-93 Hypertension (1996), 27(3 Pt 2), 786-93, Dubey et al., Hypertension (1998), 31(1 Pt 2), 516-21).        (viii) intestinal functions (Murthy et al., Journal of Neurochemistry (1995), 64(1), 77-84).        (ix) neurosecretion (Mateo et al., 1995).        (x) vascular tone (Haynes et al., American Journal of Physiology (1995), 268(5, Pt. 2), H1862-H1868).        (xi) asthma (Feoktistov et al., Trends in pharmacological sciences (1998), 19(4), 148-153; Holgate, British Journal of Pharmacology (2005), 145(8), 1009-1015).        (xii) COPD (Van den Berge et al., Drugs in R&D (2007), 8(1), 13-23).        
Thus, there remains a medical need for low molecular weight selective antagonists of the A2B receptor with pharmacokinetic and pharmacodynamic properties making them suitable for use as pharmaceutical agents. There also remains a medical need for new treatments of disorders mediated by the A2B receptor, by selective antagonism of the A2B receptor, particularly the treatment of nociception, asthma, COPD, inflammatory disorders, diabetes, diabetic retinopathy and cancer. The object of the present invention is to provide such pharmaceutical agents and treatments.
It has now been found that certain thienopyrimidine derivatives show efficacy as selective A2B antagonists.